UK Genetics of Liver Disease Consortium – ‘UK GoLD’ Representatives Dr Quentin M. Anstee, Newcastle University Prof Alastair Burt, Newcastle University Prof Jeremy Lambert, Dundee University 1 st MRC – IMPC Mouse Network Meeting, MRC Harwell, January 2012
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UK Genetics of Liver Disease Consortium – UK GoLD Representatives Dr Quentin M. Anstee, Newcastle University Prof Alastair Burt, Newcastle University Prof.
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UK Genetics of Liver Disease Consortium – ‘UK GoLD’
RepresentativesDr Quentin M. Anstee, Newcastle UniversityProf Alastair Burt, Newcastle UniversityProf Jeremy Lambert, Dundee University
• ENU-induced mutations of GABRB1 gene leads to increased alcohol consumption, increased motivation for alcohol, and increased sensitivity to alcohol.
• Mutant mice show massive increases in tonic GABA currents in accumbens medium spiny neurones that are integral to reward and motivation, suggesting that decreasing tonic GABA currents may reduce alcohol intake
• In humans, allelic differences of the GABRB1 gene were associated with alcohol dependence.
Linking Genes to Behaviour: Towards Endophenotypes
• Variations in the gene encoding 2 a subunits of GABA receptors are associated with cocaine and alcohol addiction in people.
• Deleting 2a genes in mice reduces GABA currents in accumbens medium spiny neurones by 30% and prevents cocaine’s effects on conditioned behaviours.
WT
2-/-a
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WT
2 deleted
Cocaine-facilitates conditioned reward in normal animals butnot if 2 subunits of GABA receptors are missing
Cocaine (mg/kg)
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a2 2bg
Variations in the gene for 2 a are associated with cocaine addiction in
* Dr Q.M. Anstee Newcastle University Prof A. Burt Newcastle University
* Prof C.P. Day Newcastle University * Prof A. Daly Newcastle University * Prof D. Jones Newcastle University * Prof R. Goldin Imperial College * Prof M. Thursz Imperial College * Prof S. Brown MRC Harwell * Prof R. Cox MRC Harwell * Dr P. Potter MRC Harwell
Prof D. Adams University of BirminghamDr P. Newsome University of Birmingham Dr G. Alexander Cambridge University
* MRC Harwell Liver ENU Research Programme
Research Areas
• Non-Alcoholic Fatty Liver Disease– Progressive steatohepatitis and fibrosis associated with T2DM, obesity and
the metabolic syndrome. – Tissue oxidative stress response.– Role of caspase activation in disease pathogenesis.
• Drug Induced Liver Disease & Toxicity– Idiosyncratic drug reactions– Paracetamol toxicity
GWAS Activity
• ‘FLIP’ – Fatty Liver Inhibition of Progression– FP7 funded European research programme (Anstee, Burt, Daly, Day) – GWAS of biopsy-proven NAFLD– Establish large prospective and retrospective cohorts with NAFLD,
NASH and NAFLD-related HCC for translational study.
• ‘UK PBC Consortium’ – Recently completed GWAS of PBC (Jones, Mells, Alexander)– Established the largest PBC cohort in the world for study.
• ‘GenomALC’ – Genetics of Alcoholic Liver Disease– International study, GWAS of ALD (Day)
• ‘DILIGEN’ - Drug Induced Liver Injury– GWAS of Idiosyncratic DILI across a range of agents (Daly, Day)
• The final common pathway of liver injury
Consortium Members
Modifiers of Hepatic Fibrosis and Liver Regeneration
Prof A. Burt Newcastle University
Prof D. Mann Newcastle University Dr Q.M. Anstee Newcastle University
Prof M. Thursz Imperial College
Prof R. Goldin Imperial College
Dr P. Newsome University of Birmingham
Prof D. Adams University of Birmingham
Translation from Association to Mechanism & Therapy
• Role of coagulation system activation in Liver fibrosis and stellate cell activation.
• Translational studies demonstrate that carriers of FvL mutation have accelerated fibrosis.
• This was confirmed in FvL mice and anticoagulation demonstrated to be an effected anti-fibrotic.
• On-going MRC Experimental medicine funded clinical trial (WAFT-C).
C57BL/6 FvL
H&
EAn
ti-SM
A
C57BL/6 + Warfarin
Targeting the Renin-Angiotensin System (RAS) to Treat Fibrosis
• Hepatic stellate cells have a RAS that prevents apoptosis. Drugs that induce apoptosis will stimulate fibrosis reversion despite ongoing liver injury.
UK GoLD Consortium Activity within the IMPC
• Current GWAS and hypothesis-driven research by UK GoLD members will help to guide IMPC gene prioritisation.
• UK GoLD members will establish a working group of clinicians to review IMPC clinical biochemistry data for metabolic, hepatitic and cholestatic compound phenotypes.
• Members will input into the phenotype pipelines to assess utility of screens and help guide technical development of the pipeline.
UK GoLD Consortium Activity within the IMPC
• Members will integrate with IMPC to use mice in established basic research programmes as specific knockouts become available.
• Potential UK GoLD Secondary Screens include:– Electrophysiology (in vivo and in vitro), – Addiction/motivational behaviours, – Response to environmental challenges: EtOH, HFD, ALIOS, DILI,– Fibrosis models: MCD, CCl4, Thiocetamide, BDL, etc.
• UK GoLD will institute histological screens for liver disease in selected knockout animals. – Two internationally recognised expert liver pathologists (Burt and Goldin) with